[The use of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder: theoretical and practical considerations].

In the last 2 decades, a growing body of evidence documented the efficacy and tolerability of repetitive transcranial magnetic stimulation (rTMS) in the treatment of psychiatric diseases, especially of major depressive disorder (a.k.a. unipolar depression). In our paper, we discuss briefly the historical aspects of TMS, its position among neurostimulatory methods and its mechanism of action. Then we review in details the practical aspects of the application of rTMS (e.g. stimulation parameters, contraindicatitions, side-effects) as well as the evidences of its efficacy in the treatment of depression. We also outline the possibilities of the use of rTMS in other psychiatric disorders than MDD. In our opinion, more than 10 years after receiving the FDA clearence, rTMS should be added to the Hungarian treatment guideline of MDD. Furthermore, the elaboration of the details of the insurance coverage of the rTMS treatment by the Hungarian National Health Insurance Fund would also be required.

[Investigation of the acute effect of bilateral repetitive transcranial magnetic stimulation (rTMS) in therapy resistant major depression patients]. / Bilaterális repetitív transzkraniális mágneses stimuláció (rTMS) akut hatásának vizsgálata terápia rezisztens major depresszióban szenvedok körében.

INTRODUCTION: There is a 20-year history of rTMS treatment, however, is not available in Hungary in routine clinical practice for therapy resistant depression (TRD). In this study we analysed the change of symptom profile of a Hungarian cohort with TRD using bilateral rTMS treatment. METHODS: A cohort of 22 patients suffering from TRD was enrolled in the study. For assessment of the phenotypic profile the Beck Depression Inventory (BDI), The Beck Anxiety Inventory (BAI), The Montgomery-Asberg Depression Rating Scale (MADRS), the Snaith-Hamilton Pleasure Scale (SHAPS), the Insomnia Severity Index (ISI), and the Trail Making Test were applied. Differences of mean scores of scales were compared between the day 1 (before treatment) and the day 14 (after conclusion of treatment). Furthermore, we performed phenotypic comparisons between the gender subgroups. RESULTS: In the total sample significant reduction of symptom scores was found on the depression (pMADRS=0,022; pBDI=0,001) and the anxiety scales (pBAI=0,020) and in case of the TMT-A test (pTMT-A=0,019) at the end of the treatment. The mean scores of the SHAPS, the ISI and the TMT-B did not change up to the day 14. In the sex-specific analysis we found that in men only sleep disorder was improved (p=0,015), while in women both depression scores and TMT-A score decreased significantly (MADRSp=0,015; BDIp=0,005; TMT-Ap=0,036). There were no adverse events during the rTMS treatment. CONCLUSION: 2x5 sessions of bilateral rTMS treatment is an effective, safety applicable intervention in patients with TRD. Our results suggest that significant improvement of depressive, anxious and attention symptoms can be observed already after 10th session. Our findings highlighted that different symptoms evolve in women and men due to the acute effect of the rTMS treatment. Further follow-up study is required to evaluate the long-term effect of rTMS concerning the maintenance of symptom reduction and potential change of anhedonia and insomnia.

[The practical considerations of antidepressant use during pregnancy and breastfeeding]. / Az antidepresszívumhasználat gyakorlati szempontjai a várandósság és az anyatejes táplálás idoszakában.

Main indications of antidepressants (ADs) as major depressive disorder (MDD) and different kinds of anxiety disorders are quite prevalent during pregnancy and the postpartum period. Due to the possible hazards of in utero and breast milk exposition of ADs, both psychiatrists and mothers frequently have concerns about the use of ADs during the periods of pregnancy and breastfeeding. However, we should also bear in mind that affective disorders left untreated during these periods are also associated with health risks for the mother and the baby as well. Accordingly, the treatment of affective disorders during these periods is essential. For mild cases of affective disorders the recommended treatment modality is typically psychotherapy while for the severe cases pharmacotherapy (including AD treatment) is recommended. Unfortunately, due to the lack of well-designed prospective studies, only sparse information is available on the efficacy and safety of AD treatment in pregnant and breastfeeding women. In this review we try to provide some practical advice in terms of the use of ADs during the periods in question.

[Association between the 5-HTTLPR polymorphism of the serotonin transporter gene and suicide: a case-control pilot study]. / A szerotonin transzporter gén 5-HTTLPR polimorfizmusa és az öngyilkosság összefüggése: eset-kontroll elrendezésu pilot vizsgálat.

OBJECTIVES: Besides psychological and social effects, biological, biochemical and genetic factors also play a role in the background of suicide. The aim is developing a complex model incorporating all the above factors so that suicide could be predicted and prevented in those at risk. Based on several studies 5-HTTLPR s allele frequency is increased in case of violent completed suicides. The aim of the present study was to validate this association in a sample of completed suicides. METHODS: During autopsy sample DNA samples were obtained for 5-HTTLPR genotyping from 200 subjects deceased due to suicide and 200 controls deceased due to other causes. Chi square tests and logistic regressions were performed according to additive, dominant and recessive models to analyse the possible association between 5-HTTLPR genotype distribution and suicide. RESULTS: Ratio of violent and non-violent suicides was 81% and 19% respectively. No significant difference was found in the distribution of 5-HTTLPR genotypes between the suicide and controls samples. No difference was found between violent and nonviolent suicides with respect to genotype distribution. A significant association was found between sl genotype and suicide at a younger age. CONCLUSIONS: Our pilot study did not support the supposed association between 5-HTTLPR and completed suicides or with violent completed suicides. However we found a significant association between sl genotype and suicide in young suicidals.

Maternal bonding styles in smokers and non-smokers: a comparative study.

BACKGROUND: Parental bonding has been implicated in smoking behavior, and the quality of maternal bonding (MB) has been associated with poor mental health and substance use. However, little is known about the association of MB and the smoking of the offspring. METHODS: In our study, 129 smokers and 610 non-smoker medical students completed the parental bonding instrument, which measures MB along two dimensions: care and overprotection. Four categories can be created by high and low scores on care and overprotection: optimal parenting (OP; high care/low overprotection); affectionless control (ALC; low care/high overprotection); affectionate constraint (AC; high care/high overprotection), and neglectful parenting (NP; low care/low overprotection). Nicotine dependence was assessed by the Fagerstrom Nicotine Dependence Test, exhaled CO level, and daily cigarette consumption (CPD). RESULTS: Higher CPD was significantly associated with lower overprotection (p = 0.016) and higher care (p = 0.023) scores. The odds for being a smoker were significantly higher in the neglectful maternal bonding style compared to the other rearing styles (p = 0.022). Besides, smokers showed significantly higher care and lower overprotection scores with the Mann-Whitney U-test than non-smokers, although these associations did not remain significant in multiple regression models. CONCLUSION: Our results indicate that focusing on early life relationship between patient and mother can be important in psychotherapeutic interventions for smoking. Registration trials retrospectively registered.

[Personalized medicine in psychiatry: nightmare of the industry?] / Egyénre szabott terápia: a gyógyszeripar rémálma?

Personalized medicine is a hot topic in the literature of the psychiatric field but it seems that regular clinical application of valid tests are awaited. Urgent requirement of objective tools for screening high-risk patients is postulated by prominent authors because long-term set up time, serious side effects or ineffectiveness of psychiatric agents mean a great challenge for clinicians to find optimal therapy on time. Unwanted suffering from inaccurate medicine, progression of the disorder and mistrust or in adherence of the patients are dramatic consequences of the delay of adequate therapy which is linked with irreversible health and mental damages and financial loss. On the other hand, a growing body of data are published on pharmacogenomic studies in association with psychiatric conditions. Although several pharmacogenetic tests are commercially available, accurate use of these tools are absent from clinical protocols. Here we give a short review on the most important pharmacogenomic results and a discussion on possible conflict of interests around pharmacogenetic tests. We conclude that all participants of the health care system could benefit from personalized medicine in psychiatry.

Catatonia in disulfiram intoxication - a case report and a brief overview of the literature.

Catatonic syndromes could accompany a variety of psychiatric and medical conditions. The most common conditions underlying catatonia are affective disorders followed by schizophrenia, but several medical conditions including intoxications affecting the central nervous system can also present with catatonic signs and symptoms. Therapeutic doses of disulfiram could induce catatonia with or without accompanying psychosis or mood disorder. A case of disulfiram intoxication manifesting with catatonia is reported here together with a brief overview of the literature. A patient was admitted to the toxicology ward after a suicide attempt with approximately 20 g of disulfiram. On transfer to the psychiatric ward, she was sitting still, in a semi-stuporous state and displayed motiveless resistance to instructions or attempts to move (active negativism). She was unresponsive to most of the questions (mutism), occasionally verbigerated 1-2 words and stared for more than 20 seconds between shifting attention. After developing a comatosus state her treatment continued at the toxicology ward, where a contrast-enhanced computer tomography scan revealed bilateral emollition of 1.5 cm diameter in both nucleus lentiformis at the level of the third ventricle. Following treatment her condition improved and she benefited of rehabilitation facility and a second psychiatric treatment. She was discharged free of neurological and psychiatric symptoms. In conclusion, we underscore the importance of accurate diagnosis of the underlying psychiatric or medical condition when encountering a fast emerging catatonic syndrome and focus first on treating the causative condition while simultaneously attempting symptomatic treatment of catatonia.

[An update on the conceptual and classification issues of anxiety, its neuroanatomy and problems of anxiolytic drug discovery]. / A szorongás konceptuális aspektusai, klasszifikációja, neuroanatómiája és az anxiolítikum-fejlesztés problémái.

Anxiety disorders are highly prevalent psychiatric diseases. In this short review we provide an overview of concepts of fear, anxiety and anxiety disorders. In addition, based on the recent literature, neuroanatomical structures involved in anxiety and functional/structural changes of these structures in anxiety disorders are also discussed. Furthemore, the pitfalls of anxiolytic drug discovery is also concerned in the paper.

[Emergency psychopharmacotherapy in Hungary -- preliminary data]. / Sürgosségi pszichofarmakoterápia Magyarországon -- elozetes adatok.

OBJECTIVES: Although the number of patients admitted for psychiatric emergency care is increasing according to data from various countries, there are no large-scale studies assessing clinical emergency practice and in several countries no national guidelines have been published concerning emergency care in psychiatry. The aim of our study was to assess practice related to emergency care of agitated-psychotic patients in Hungary. METHODS: Anonymous survey questionnaire with questions related to care of an agitated patient showing psychotic symptoms was dispatched to 210 institutions providing psychiatric care in Hungary in 2013. RESULTS: The overwhelming majority of the 155 participating clinicians would use haloperidol (92.9%) and benzodiazepines (81.3%), 74.8% in a dual combination. 18.7% would apply monotherapy and 5.2% a triple combination of medications. 59.4% would use i.v. and 23.9% i.m. therapy, and 9% would apply the combination of these two. In case of failure of first-line therapy, 76.8% of participants would repeat the previous medication. CONCLUSIONS: The aim of our study was to assess emergency interventions in psychiatry focusing on different psychopharmacological approaches. Our results provide a cross-sectional view on current practice in Hungary, and therefore may contribute to outlining practice-coherent guidelines and also provide the opportunity for a comparison with international trends.

[Catatonia and neuroleptic malignant syndrome in view of a psychopathological and pathophysiological overlap: a brief review]. / Katatónia és neuroleptikus malignus szindróma a pszichopatológiai és patofiziológiai átfedések tükrében: rövid összefoglaló tanulmány.

Catatonia was first described in the 19th century as a syndrome with motor, affective and behavioral symptoms. During the 20th century it was rather regarded as a rare motoric manifestation of schizophrenia and that classification has almost resulted in the disappearance of catatonia among patients outside of the schizophrenia spectrum. With the introduction of neuroleptics, the incidence of catatonic schizophrenia also declined which was attributed to effective treatment. Simultaneously, neuroleptic malignant syndrome was described, which shows many similarities with catatonia. Recently, several researchers suggested a common origin of the two disorders. In this paper we review case reports of the last five years, in which both neuroleptic malignant syndrome and catatonia had emerged as a diagnosis. Additionally, based on the relevant literature, we propose a common hypothetical pathomechanism with therapeutic implications for the two syndromes. Besides underlining the difficulties of differential diagnosis, the reviewed cases demonstrate a transition between the two illnesses. The similarities and the possible shifts may suggest a neuropathological and pathophysiological overlap in the background of the two syndromes. Electroconvulsive therapy and benzodiazepines seem to be an effective treatment in both syndromes. These two treatment approaches can be highly valuable in clinical practice, especially if one considers the difficulties of differential diagnosis.

Glycogen synthase kinase 3 beta gene structural variants as possible risk factors of bipolar depression.

The glycogen synthase kinase 3B (GSK3B) is an important target protein of several antidepressants, such as lithium, a mood stabilizer. Recent studies associated structural variations of the GSK3B gene to bipolar disorder (BP), although replications were not conclusive. Here we present data on copy number variations (CNVs) of the GSK3B gene probing the 9th exon region in 846 individuals (414 controls, 172 patients with major depressive disorder (MDD) and 260 with BP). A significant accumulation (odds ratio: 5.5, P = 0.00051) of the amplified exon 9 region was found in patients (22 out of 432) compared to controls (4 of 414). Analyzing patient subgroups, GSK3B structural variants were found to be risk factors of BP particularly (P = 0.00001) with an odds ratio of 8.1 while no such effect was shown in the MDD group. The highest odds (19.7 ratio) for bipolar disorder was observed in females with the amplified exon 9 region. A more detailed analysis of the identified GSK3B CNV by a set of probes covering the GSK3B gene and the adjacent NR1I2 and C3orf15 genes showed that the amplified sequences contained 3' (downstream) segments of the GSK3B and NR1I2 genes but none of them involved the C3orf15 gene. Therefore, the copy number variation of the GSK3B gene could be described as a complex set of structural variants involving partial duplications and deletions, simultaneously. In summary, here we confirmed significant association of the GSK3B CNV and bipolar disorder pointing out that the copy number and extension of the CNV varies among individuals.

[Adult psychiatric aspects of Niemann-Pick disease]. / A Niemann-Pick betegség felnött pszichiátriai vonatkozásai.

Niemann-Pick disease (NPD) is a group of distinct rare disorders (i.e. NPD-A; NPD-B; NPD-C) - with autosomal recessive inheritance pattern - within the class of the inborn disorders of the sphingolipid metabolism (called sphingolipidoses). Since patients with NPD-A do not survive into adulthood and most patients with NPD-B are free from neuropsychiatric symptoms we discuss only briefly type-A and -B NPD and mainly constrict our review discussing the neuropsychiatric symptoms along with the pathomechanism and the treatment of NPD-C. NPD-C is clinically heterogeneous, with notable variations in age at onset, course and symptoms. Along with systemic signs, neurologic and psychiatric symptoms are quite frequent in NPD-C and in its adult form sometimes psychiatric symptoms are the first ones appearing. Unfortunately, the majority of clinicans (including adult psychiatrists and neurologists) are not aware of the symptom group characteristic to NPD-C so patients with this disorder are frequently misdiagnosed in the clinical practice. Since neuropsychiatric manifestations of NPD-C may be treated with a substrate reduction agent (miglustat) with greater awareness of the identification of neuropsychiatric symptoms in due course is the prerequisite of proper and early diagnosis and treatment.

[Association between mood characteristics and polymorphisms of glial cell line-derived neurotrophic factor (GNDF) in patients with depression]. / A hangulati dimenziók és a glia-eredetü növekedési faktort kódoló gén polimorfizmusainak összefüggése depresszióval diagnosztizált mintán.

Glial cell line-derived neurotrophic factor (GNDF) plays an important role in the development and synaptic plasticity of dopaminergic neurons, thus it could be an important therapeutic factor in Parkinson's disease. Results from candidate gene studies of GDNF in psychiatric disorders are contradictory. Moreover, the possible association between GDNF polymorphisms and major- or bipolar depression has not been studied to date. Recently, our research group has published an association between two GDNF polymorphisms (rs3812047, rs3096140) and the individual variability of anxiety measured by the Hospital Anxiety and Depression Scale (HADS) on a non-clinical sample. In the present study we further analyzed this association on a sample with major- and bipolar depression: we used data from 183 MDD, 116 BP, and 1172 control subjects and tested effect of GDNF rs3812047 and rs3096140 polymorphisms on mood disorders. The case control design did not show significant differences in the genotype distribution of BP or MDD versus control patients. However, in the bipolar group subjects with rs3812047 A allele showed a significantly higher anxiety and depression mean score then subjects with G allele (p=0.043). This result supports our previous findings demonstrated on a non-clinical sample. Interestingly we found an opposite effect of the rs3812047 using data from MDD patients: subjects with the G allele had higher depression scores (p=0.012). An interaction effect of patient subgroups and genetic variants of the rs3812047 was observed for both HADS subscales (anxiety: p=0.029; depression: 0.004). In summary, we confirmed the previously published association between the rs3812047 A allele and mood characteristics on the bipolar sample, and an effect in the opposite direction was detected in the patient group with major depression.

Pharmaco- and therapygenetic aspects in the treatment of anxiety disorders beyond the serotonergic system: a brief review.

Anxiety disorders (ADs) are among the most frequent psychiatric disorders. In addition, key features of ADs include that they are among the earliest mental disorders to manifest and that their first specific treatment frequently occurs several years after the onset of symptoms. Although the heritability of anxiety disorders is well known, the genetic determination of response to different modalities (psycho- or pharmacotherapy) used in treatment of patients with ADs is lesser investigated. Several studies focused on the role of serotonergic genes in the etiopathology and pharmacotherapy of anxiety disorders, however, less attention was paid to variants of other genes. In this review we focus on the cytochrome P 450, BDNF, COMT, MAOA, EAA-3 transporter, dopamine transporter and dopamine receptor gene polymorphisms and their effects with respect to the pharmacogenetics of anxiety disorders. We discuss the current knowledge on pharmacogenetic/therapygenetic aspects of anxiety disorders beyond the serotonergic system.

Pharmacogenetics of antidepressive drugs: a way towards personalized treatment of major depressive disorder.

Major depressive disorder is one of the most prevalent psychiatric disorders, and in spite of extensive ongoing research, we neither fully understand its etiopathological background, nor do we possess sufficient pharmacotherapeutic tools to provide remission for all patients. Depression is a heterogenous phenomenon both in its manifestation and its biochemical and genetic background with multiple systems involved. Similarly, the employed pharmaceutical agents in the treatment of depression also effect multiple neurotransmitter systems in the brain. However, we do not yet possess sufficient tools to be able to choose the medication that treats the symptoms most effectively while contributing to minimal side effects in parallel and thus provide personalized pharmacotherapy for depression. In the present paper we review genetic polymorphisms that may be involved in the therapeutic effects and side effects of antidepressive medications and which, in the future, may guide customized selection of the pharmacotherapeutic regimen in case of each patient.

Change of Circulating Vascular Endothelial Growth Factor Level and Reduction of Anhedonia Are Associated in Patients With Major Depressive Disorder Treated With Repetitive Transcranial Magnetic Stimulation.

Aim: Vascular endothelial growth factor (VEGF) has been implicated in mediating the effect of antidepressant therapies as it plays a significant role in the neurogenesis. Anhedonia, an endophenotype of major depressive disorder (MDD), is related to the dorsolateral prefrontal cortex, the major focus of brain stimulation in MDD. The aim of our study was to analyze the change of serum VEGF level after rTMS treatment in association with anhedonia. Materials and Methods: A dataset of 17 patients with TRD who were treated with antidepressants and bilateral rTMS for 2 × 5 days was analyzed. Depression was measured by the Montgomery-Asberg Depression Scale (MADRS) and anhedonia by the Snaith-Hamilton Pleasure Scale (SHAPS) for monitoring the symptom changes. The serum VEGF levels and symptoms were assessed on the first (V1), on the 14th (V2), and on the 28th day (V3). The level of VEGF was measured by ELISA assay. Results: There was no significant association between MADRS scores and serum VEGF levels at any timepoint. The decrease in the SHAPS score was significantly associated with the increase in VEGF level between V1 and V2 (p = 0.001). The VEGF levels were significantly higher in non-responders than in responders (p = 0.04). The baseline VEGF level has been proven as a significant predictor of treatment response (p = 0.045). Conclusion: Our results suggest that serum VEGF can be sensitive to the changes of anhedonia during rTMS treatment. Considering that the most widely used depression scales are not applicable for the assessment of anhedonia, measurement of anhedonia in rTMS treatment studies of patients with TRD can be suggested as more appropriate data on distinct pathogenic pathways and specific biomarkers of the disorder.

Genetic and pharmacogenomic data on smoking: the bigger sample size, the less reliable phenotype? A critical review.

Increasing amount of genetic data on nicotine dependence (ND) is available in the literature, sometimes extremely large population size is reported but the study design is not always consequent. Phenotypic measures can vary from a simple 6-item self-rating scale to breath CO or serum cotinine level test but in genetic investigations this is not sophisticated; moreover the population stratification is also usually ignored. In contrast, possibly because of the strict traditions of pharmacological investigations, pharmacogenomic studies on smoking cessation therapy use more reliable phenotypic measures with high quality design consequently involving fewer participants. In spite of the heavy epidemiological data on smoking in Hungary, genetic background of heavy smoking is still not studied in this population. In this review we sum up the most important, replicated results but we also provide some critical remarks about the methodological shortcomings of these studies. Keeping in mind the value of large scale population ND association studies we would also like to emphasize that the clinical implementation of studies with larger samples but with weaker methodology and statistical analyses is limited. Similar to many other psychiatric disorders, ND is a multifactorial condition, therefore the measure of genetic effects requires a more complex study design.

Origins and perspectives of schizophrenia research.

Schizophrenia is a complex psychiatric disorder with a heterogeneous clinical phenotype. Ancient paradigms focused on clinical experiences and hypotheses mostly without validated measurements but in the modern neuroscientific era the trend has turned oppositely; although an expanding body of evidence is available in association with the neurobiological background of schizophrenia, it seems that development of phenotypic description has been missing from the focus. However, now it is clear that a relevant and sophisticated diagnostic system is also essential for the appropriate interpretation of comprehensive molecular studies. Besides a brief review of most important data on schizophrenia research, the authors call attention to a complex diagnostic system (Composite Diagnostic Evaluation, CODE) which can be a valuable clinical partner of currently accepted models of schizophrenia, such as the neurodevelopmental hypothesis.

[Clinical characteristics of cannabis-induced schizophrenia spectrum disorder]. / Kannabiszhasználat mellett kialakuló szkizofréniaspektrum-zavar klinikai jellegzetességeinek vizsgálata.

Marijuana (cannabis) is the most commonly abused drug by adolescents and young adults and also by people with schizophrenia or other psychotic disorders. An increasing number of studies suggest that regular cannabis users can show psychotic episodes similar to schizophrenic disorders but it still unclear if cannabis induced psychotic disorder is a distinct entity requiring special therapy or regular cannabis use consequently leads to schizophrenia. Therefore, we retrospectively compared psychotic patients with and without cannabis use by clinical profile. Clinical data of 85 patients with schizophrenia spectrum disorder were analyzed retrospectively. Cannabis use was not reported by 43 persons (Cnbs0 subgroup) and 42 patients used regularly cannabis during at least 1 year (Cnbs1 subgroup). Clinical data were collected from electronic medical documentation of patients concerning anamnesis, family history, socio-demographic condition, symptoms and psychiatric state, acute and long-term therapies. Men were over-represented in the cannabis abuser group while mean age was lower among them compared to the Cnbs0 subgroup. Prevalence of suicidal attempts was increased in men without cannabis use. Patients without cannabis use spent more time in hospital and smoking was more frequent among them. Positive and negative symptoms and family history did not differ significantly between the two subgroups. Dosage, intensity and length of pharmacotherapy was different between the two subgroups. These results revealed that certain clinical aspects were different in case of cannabis-related schizophrenia spectrum disorder compared to schizophrenia.

Peripheral endocannabinoid serum level in association with repetitive transcranial magnetic stimulation (rTMS) treatment in patients with major depressive disorder.

Repetitive transcranial magnetic stimulation (rTMS) is an effective and well tolerable biological intervention in major depressive disorder (MDD) contributing to rapid symptom improvement. Molecular mechanisms underpinning the therapeutic effects of rTMS have still not been clarified. Recently published animal data implicated relevant associations with changes in endocannabinoid (eCB) brain levels during rTMS treatment, human studies, however, have not been published. In our study we assessed the detailed phenotypic spectrum of MDD and serum 2-arachidnoylglycerol (2-AG) and anandamide (AEA) levels in 18 patients with treatment-resistant depression before, immediately following, and two weeks after completion of a 10-day rTMS treatment. We found significant associations between serum 2-AG level changes from pretreatment to 2 weeks after treatment and symptom reduction. The greater the increase of 2-AG levels, the greater the improvement of depressive (p = 0.031), anxious (p = 0.007) and anhedonia symptoms (p = 0.047). Here we report for the first time a significant association of human circulating eCB and antidepressant effect of rTMS. Our data may indicate that direct stimulation of targeted brain areas can rapidly alleviate depressive complaints via activation of the eCB system.